It is known that microparticle drug carriers including liposome formulations as a typical example and polypeptides of protein preparations and the like have poor retention in blood after intravenous administration and are readily captured by the reticuloendothelial system (henceforth abbreviated as “RES”) of liver, spleen and the like. The presence of RES is a serious obstacle when preparations are utilized such as targeting type preparations which can deriver medicaments to organs other than RES, or microparticle drug carriers as sustained release type preparations which can provide long term blood retention of medicaments and achieve control release of the medicaments.
Researches have been conducted so far to impart microcirculatability to the aforementioned preparations. For example, from a standpoint that physicochemical properties of lipid bimolecular membranes of liposomes are relatively easily controllable, some methods have been proposed such as a method of increasing blood level of liposomes by using a smaller size of liposomes (Biochimica et Biophysica Acta, vol. 761, p. 142, 1983), a method of using lecithin having a high phase transition temperature (Biochemical Pharmacology, vol. 32, p. 3381, 1983), a method of using sphingomyelin instead of lecithin (Biochemical Pharmacology, vol. 32 volumes, p. 3381, 1983), and a method of adding cholesterol as a membrane component of liposomes (Biochimica et Biophysica Acta, vol. 761, p. 142, 1983). However, among the aforementioned methods, no method is known to successfully provide microparticle drug carrier which has excellent retention in blood and is hardly taken up by RES.
As other solutions, researches have been conducted for imparting microcirculatability and avoiding RES by membrane surfaces modification of liposomes with glycolipids, glycoproteins, amino acid lipids, polyethylene glycol lipids or the like. For example, those reported as substances for such modification include glycophorin (Pharmaceutical Society of Japan, 106th Annual Convention, Lecture Abstracts, p. 336, 1986), ganglioside GM1 (FEBS letter, vol. 223, p. 42, 1987), phosphatidylinositol (FEBS Letter, vol. 223, p. 42, 1987), glycophorin and ganglioside GM3 (Japanese Patent Unexamined Publication (Kokai) No. 63-221837), polyethylene glycol derivative (FEBS Letter, vol. 268, p. 235, 1990), glucuronic acid derivative (Chemical and Pharmaceutical Bulletin, vol. 38, p. 1633, 1990), glutamic acid derivative (Biochimica et Biophysica Acta, vol. 1108, p. 257, 1992), polyglycerin phospholipid derivative (Japanese Patent Unexamined Publication No. 6-228012) and the like.
As for the modification of polypeptide, introduction of two water-soluble polymer molecules by using triazine and other methods have been reported in order to reduce binding sites of a polypeptide and thereby increase an amount of remaining active groups such as lysine residues in the polypeptide. Also as for liposome preparations, a method is reported in which two water-soluble polymer molecules are introduced into triazine to increase molecular weight of the water-soluble polymers, and liposome surfaces are modified by using the polymers. The number of the water-soluble polymers in said modification is limited up to 2. It is considered that, in this attempt, an effect of imparting microcirculatability to liposome surfaces is lower than liposomes with the hydrophilic groups. Furthermore, although phospholipid derivatives containing a polyalkylene oxide group have been used also as surfactants, no derivative has been known which is highly safe for living bodies and stably usable under a high salt concentration condition.